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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Transcriptional coactivators that modify histones represent an increasingly important group of regulatory factors, although their ability to modify other factors as well precludes common assumptions that they necessarily act by histone modification. In an extension of previous studies showing a role for acetyltransferase p300/CBP in p53 function, we have used systems reconstituted with recombinant chromatin templates and (co)activators to demonstrate (1) the additional involvement of protein arginine methyltransferases PRMT1 and CARM1 in p53 function; (2) both independent and ordered cooperative functions of p300, PRMT1, and CARM1; and (3) mechanisms that involve direct interactions with p53 and, most importantly, obligatory modifications of corresponding histone substrates. ChIP analyses have confirmed the ordered accumulation of these (and other) coactivators and cognate histone modifications on the GADD45 gene following ectopic p53 expression and/or UV irradiation. These studies thus define diverse cofactor functions, as well as underlying mechanisms involving distinct histone modifications, in p53-dependent gene activation.
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PMID:Ordered cooperative functions of PRMT1, p300, and CARM1 in transcriptional activation by p53. 1518 70

The promyelocytic leukaemia (PML) tumour-suppressor protein potentiates p53 function by regulating post-translational modifications, such as CBP-dependent acetylation and Chk2-dependent phosphorylation, in the PML-Nuclear Body (NB). PML was recently shown to interact with the p53 ubiquitin-ligase Mdm2 (refs 4-6); however, the mechanism by which PML regulates Mdm2 remains unclear. Here, we show that PML enhances p53 stability by sequestering Mdm2 to the nucleolus. We found that after DNA damage, PML and Mdm2 accumulate in the nucleolus in an Arf-independent manner. In addition, we found that the nucleolar localization of PML is dependent on ATR activation and phosphorylation of PML by ATR. Notably, in Pml(-/-) cells, sequestration of Mdm2 to the nucleolus was impaired, as well as p53 stabilization and the induction of apoptosis. Furthermore, we demonstrate that PML physically associates with the nucleolar protein L11, and that L11 knockdown impairs the ability of PML to localize to nucleoli after DNA damage. These findings demonstrate an unexpected role of PML in the nucleolar network for tumour suppression.
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PMID:PML regulates p53 stability by sequestering Mdm2 to the nucleolus. 1519

There is much interest in recent years in the possible role of different nuclear compartments and subnuclear domains in the regulation of gene expression, signalling, and cellular functions. The nucleus contains inositol phosphates, actin and actin-binding proteins and myosin isoforms, multiple protein kinases and phosphatases targeting Cdk-1 and Cdk-2, MAPK/SAPK, and Src-related kinases and their substrates, suggesting the implication of several signalling pathways in the intranuclear organization and function of nuclear bodies (NBs). NBs include the well-characterized Cajal bodies (CBs; or coiled bodies), the nucleolus, perinucleolar and perichromatin regions, additional NBs best illustrated by the promyelocytic leukemia nuclear bodies [PML-NBs, also named PML oncogenic dots (PODs), ND10, Kr-bodies] and similar intranuclear foci containing multi-molecular complexes with major role in DNA replication, surveillance, and repair, as well as messenger RNA and ribosomal RNA synthesis and assembly. Chromatin modifying proteins, such as the CBP acetyltransferase and type I histone deacetylase, accumulate at PML-NBs. PML-NBs and Cajal bodies are very dynamic and mobile within the nuclear space and are regulated by cellular stress (heat shock, apoptosis, senescence, heavy metal exposure, viral infection, and DNA damage responses). NBs strongly interact, using signalling mechanisms for the directional and ordered traffic of essential molecular components. NBs organize the delivery and storage of essential RNAs and proteins that play a role in transcription, pre-mRNA biosynthesis and splicing, and the sequestration and/or degradation of regulatory proteins, such as heterogenous nuclear ribonuclear proteins (hnRNPs), p53, Rb1, CBP, STAT3, and others. The objective of this review is to summarize some aspects of these nuclear structures/bodies/domains, including their proposed roles in cellular signalling and in human diseases, mainly neurodegenerative disorders and cancer.
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PMID:Nuclear bodies and compartments: functional roles and cellular signalling in health and disease. 1524 4

Simian virus 40 (SV40) large T antigen (T Ag) interacts with the tumor suppressor p53 and the transcriptional coactivators CBP and p300. Binding of these cellular proteins in a ternary complex has been implicated in T Ag-mediated transformation. It has been suggested that the ability of CBP/p300 to modulate p53 function underlies p53's regulation of cell proliferation and tumorigenesis. In this study, we provide further evidence that CBP activity may be mediated through its synergistic action with p53. We demonstrate that SV40 T Ag is acetylated in vivo in a p53-dependent manner and T Ag acetylation is largely mediated by CBP. The acetylation of T Ag is dependent on its interaction with p53 and on p53's interaction with CBP. We have mapped the site of acetylation on T Ag to the C-terminal lysine residue 697. This acetylation site is conserved between the T antigens of the human polyomaviruses JC and BK, which are also known to interact with p53. We show that both JC and BK T antigens are also acetylated at corresponding sites in vivo. While other proteins are known to be acetylated by CBP/p300, none are known to depend on p53 for acetylation. T Ag acetylation may provide a regulatory mechanism for T Ag binding to a cellular factor or play a role in another aspect of T Ag function.
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PMID:p53 targets simian virus 40 large T antigen for acetylation by CBP. 1525 96

The pleiotropic cytokine transforming growth factor-beta (TGF-beta) is a potent inducer of collagen synthesis and is implicated in the pathogenesis of fibrosis. Acting in concert with transcriptional coactivators p300/CBP, the Smads mediate TGF-beta stimulation of collagen synthesis in human dermal fibroblasts. Little information exists regarding positive and negative modulation of physiological TGF-beta responses. Because the tumor suppressor p53 is implicated in connective tissue homeostasis, here we examined the regulation of collagen gene expression by p53. Forced expression of ectopic p53 in dermal fibroblasts repressed basal and TGF-beta-stimulated collagen gene expression, whereas the absence of cellular p53 was associated with significantly enhanced transcriptional activity of the Type I collagen gene (COL1A2) and collagen synthesis. Ectopic expression of p53 also repressed TGF-beta stimulation of promoter activity driven by minimal Smad-binding elements, suggesting that p53 modulated Smad-dependent intracellular signaling. Inhibition was not due to altered levels, phosphorylation, or nuclear translocation of cellular Smads. Treatment of fibroblasts with etoposide, a potent inducer of cellular p53, abrogated TGF-beta stimulation of COL1A2 promoter activity and collagen synthesis in a p53-dependent manner. Overexpression of the transcriptional coactivator p300 rescued TGF-beta stimulation of COL1A2 promoter activity in fibroblasts overexpressing p53. Furthermore, the ligand-induced interaction of cellular Smad3 with p300 or with its cognate Smad-binding DNA element and recruitment of p300 to the DNA-protein complex assembled on the Smad-binding element were markedly reduced in p53-overexpressing fibroblasts. Collectively, these results indicate, for the first time, that p53 is a potent and selective endogenous repressor of TGF-beta-regulated collagen gene expression in dermal fibroblasts. The ligand-dependent interaction of Smad3 with p300 may be one of the targets of p53-mediated inhibition of TGF-beta responses. These findings suggest that a novel and important physiologic function for the tumor suppressor p53 is the regulation of fibrotic cellular responses.
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PMID:The tumor suppressor p53 abrogates Smad-dependent collagen gene induction in mesenchymal cells. 1534 15

Lysine acetylation has been shown to occur in many protein targets, including core histones, about 40 transcription factors and over 30 other proteins. This modification is reversible in vivo, with its specificity and level being largely controlled by signal-dependent association of substrates with acetyltransferases and deacetylases. Like other covalent modifications, lysine acetylation exerts its effects through "loss-of-function" and "gain-of-function" mechanisms. Among the latter, lysine acetylation generates specific docking sites for bromodomain proteins. For example, bromodomains of Gcn5, PCAF, TAF1 and CBP are able to recognize acetyllysine residues in histones, HIV Tat, p53, c-Myb or MyoD. In addition to the acetyllysine moiety, the flanking sequences also contribute to efficient recognition. The relationship between acetyllysine and bromodomains is reminiscent of the specific recognition of phosphorylated residues by phospho-specific binding modules such as SH2 domains and 14-3-3 proteins. Therefore, lysine acetylation forges a novel signaling partnership with bromodomains to govern the temporal and spatial regulation of protein functions in vivo.
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PMID:Lysine acetylation and the bromodomain: a new partnership for signaling. 1538 40

The expression of adenovirus serotype 2 or 5 (Ad2/5) E1A sensitizes cells to killing by NK cells and activated macrophages, a property that correlates with the ability of E1A to bind the transcriptional coadaptor proteins p300-CBP. The E6 oncoproteins derived from the high-risk human papillomaviruses (HPV) interact with p300 and can complement mutant forms of E1A that cannot interact with p300 to induce cellular immortalization. Therefore, we determined if HPV type 16 (HPV16) E6 could sensitize cells to killing by macrophages and NK cells. HPV16 E6 expression sensitized human (H4 and C33A) and murine (MCA-102) cell lines to lysis by macrophages but not by NK cells. The lysis of cells that expressed E6 by macrophages was p53 independent but dependent on the production of tumor necrosis factor alpha (TNF-alpha) or nitric oxide (NO) by macrophages. Unlike cytolysis assays with macrophages, E6 expression did not significantly sensitize cells to lysis by the direct addition of NO or TNF-alpha. Like E1A, E6 has been reported to sensitize cells to lysis by TNF-alpha by inhibiting the TNF-alpha-induced activation of NF-kappaB. We found that E1A, but not E6, blocked the TNF-alpha-induced activation of NF-kappaB, an activity that correlated with E1A-p300 binding. In summary, Ad5 E1A and HPV16 E6 sensitized cells to lysis by macrophages. Unlike E1A, E6 did not block the ability of TNF-alpha to activate NF-kappaB or sensitize cells to lysis by NK cells, TNF-alpha, or NO. Thus, there appears to be a spectrum of common and unique biological activities that result as a consequence of the interaction of E6 or E1A with p300-CBP.
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PMID:Macrophages kill human papillomavirus type 16 E6-expressing tumor cells by tumor necrosis factor alpha- and nitric oxide-dependent mechanisms. 1559 7

p53-dependent apoptosis is a major determinant of its tumor suppressor activity and can be triggered by hypoxia. No p53 target is known to be induced by p53 or to mediate p53-dependent apoptosis during hypoxia. We report that p53 can directly upregulate expression of Bnip3L, a cell death inducer. During hypoxia, Bnip3L is highly induced in wild-type p53-expressing cells, in part due to increased recruitment of p53 and CBP to Bnip3L. Apoptosis is reduced in hypoxia-exposed cells with functional p53 following Bnip3L knockdown. In vivo, Bnip3L knockdown promotes tumorigenicity of wild-type versus mutant p53-expressing tumors. Thus, Bnip3L, capable of attenuating tumorigenicity, mediates p53-dependent apoptosis under hypoxia, which provides a novel understanding of p53 in tumor suppression.
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PMID:Bnip3L is induced by p53 under hypoxia, and its knockdown promotes tumor growth. 1560 64

Despite a wealth of knowledge regarding the early steps of epithelial differentiation, little is known about the mechanisms responsible for terminal nephron differentiation. The bradykinin B2 receptor (B2R) regulates renal function and integrity, and its expression is induced during terminal nephron differentiation. This study investigates the transcriptional regulation of the B2R during kidney development. The rat B2R 5'-flanking region has a highly conserved cis-acting enhancer in the proximal promoter consisting of contiguous binding sites for the transcription factors cAMP response element binding protein (CREB), p53, and Kruppel-like factor (KLF-4). The B2R enhancer drives reporter gene expression in inner medullary collecting duct-3 cells but is considerably weaker in other cell types. Site-directed mutagenesis and expression of dominant negative mutants demonstrated the requirement of CREB DNA binding and Ser-133 phosphorylation for optimal enhancer function. Moreover, helical phasing experiments showed that disruption of the spatial organization of the enhancer inhibits B2R promoter activity. Several lines of evidence indicate that cooperative interactions among the three transcription factors occur in vivo during terminal nephron differentiation: 1) CREB, p53, and KLF-4 are coexpressed in B2R-positive differentiating cells; 2) the maturational expression of B2R correlates with CREB/p53/KLF-4 DNA-binding activity; 3) assembly of CREB, p53, and KLF-4 on chromatin at the endogenous B2R promoter is developmentally regulated and is accompanied by CBP recruitment and histone hyperacetylation; and 4) CREB and p53 occupancy of the B2R enhancer is cooperative. These results demonstrate that combinatorial interactions among the transcription factors, CREB, p53, and KLF-4, and the coactivator CBP, may be critical for the regulation of B2R gene expression during terminal nephron differentiation.
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PMID:Combinatorial control of the bradykinin B2 receptor promoter by p53, CREB, KLF-4, and CBP: implications for terminal nephron differentiation. 1582 Dec 54

Chromosomal rearrangements associated with acute myeloid leukemia (AML) include fusions of the genes encoding the acetyltransferase MOZ or MORF with genes encoding the nuclear receptor coactivator TIF2, p300, or CBP. Here we show that MOZ-TIF2 acts as a dominant inhibitor of the transcriptional activities of CBP-dependent activators such as nuclear receptors and p53. The dominant negative property of MOZ-TIF2 requires the CBP-binding domain (activation domain 1 [AD1]), and coimmunoprecipitation and fluorescent resonance energy transfer experiments show that MOZ-TIF2 interacts with CBP directly in vivo. The CBP-binding domain is also required for the ability of MOZ-TIF2 to extend the proliferative potential of murine bone marrow lineage-negative cells in vitro. We show that MOZ-TIF2 displays an aberrant nuclear distribution and that cells expressing this protein have reduced levels of cellular CBP, leading to depletion of CBP from PML bodies. In summary, our results indicate that disruption of the normal function of CBP and CBP-dependent activators is an important feature of MOZ-TIF2 action in AML.
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PMID:MOZ-TIF2 inhibits transcription by nuclear receptors and p53 by impairment of CBP function. 1565 27


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